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https://www.readbyqxmd.com/read/28817800/tia1-mutations-in-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia-promote-phase-separation-and-alter-stress-granule-dynamics
#1
Ian R Mackenzie, Alexandra M Nicholson, Mohona Sarkar, James Messing, Maria D Purice, Cyril Pottier, Kavya Annu, Matt Baker, Ralph B Perkerson, Aishe Kurti, Billie J Matchett, Tanja Mittag, Jamshid Temirov, Ging-Yuek R Hsiung, Charles Krieger, Melissa E Murray, Masato Kato, John D Fryer, Leonard Petrucelli, Lorne Zinman, Sandra Weintraub, Marsel Mesulam, Julia Keith, Sasha A Zivkovic, Veronica Hirsch-Reinshagen, Raymond P Roos, Stephan Züchner, Neill R Graff-Radford, Ronald C Petersen, Richard J Caselli, Zbigniew K Wszolek, Elizabeth Finger, Carol Lippa, David Lacomis, Heather Stewart, Dennis W Dickson, Hong Joo Kim, Ekaterina Rogaeva, Eileen Bigio, Kevin B Boylan, J Paul Taylor, Rosa Rademakers
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10(-6)). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions...
August 16, 2017: Neuron
https://www.readbyqxmd.com/read/28817753/efficacy-and-safety-of-durvalumab-in-locally-advanced-or-metastatic-urothelial-carcinoma-updated-results-from-a-phase-1-2-open-label-study
#2
Thomas Powles, Peter H O'Donnell, Christophe Massard, Hendrik-Tobias Arkenau, Terence W Friedlander, Christopher J Hoimes, Jae Lyun Lee, Michael Ong, Srikala S Sridhar, Nicholas J Vogelzang, Mayer N Fishman, Jingsong Zhang, Sandy Srinivas, Jigar Parikh, Joyce Antal, Xiaoping Jin, Ashok K Gupta, Yong Ben, Noah M Hahn
Importance: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. Objective: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. Design, Setting, and Participants: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein...
August 17, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28817750/the-surgeon-on-service-model-for-timely-economically-viable-inpatient-care-of-tracheostomy-patients-in-academic-pediatric-otolaryngology
#3
Jennifer M Lavin, James W Schroeder, Dana M Thompson
Importance: The traditional practice model for pediatric otolaryngologists at high-volume academic centers is to simultaneously balance outpatient care responsibilities with those of the inpatient service, emergency department, and ambulatory care clinics. This model leads to challenges with care coordination, timeliness of nonemergency operative care, and consistent participation in care and consultation at the attending surgeon level. The "surgeon on service" (SOS) model-where faculty members rotate to manage the inpatient service in lieu of outpatient responsibilities-has been described as one method to address this conundrum...
August 17, 2017: JAMA Otolaryngology—Head & Neck Surgery
https://www.readbyqxmd.com/read/28817711/on-chip-detection-of-gel-transition-temperature-using-a-novel-micro-thermomechanical-method
#4
Tsenguun Byambadorj, Erfan Dashtimoghadam, Mohamadali Malakoutian, Benyamin Davaji, Lobat Tayebi, James E Richie, Chung Hoon Lee
We present a new thermomechanical method and a platform to measure the phase transition temperature at microscale. A thin film metal sensor on a membrane simultaneously measures both temperature and mechanical strain of the sample during heating and cooling cycles. This thermomechanical principle of operation is described in detail. Physical hydrogel samples are prepared as a disc-shaped gels (200 μm thick and 1 mm diameter) and placed between an on-chip heater and sensor devices. The sol-gel transition temperature of gelatin solution at various concentrations, used as a model physical hydrogel, shows less than 3% deviation from in-depth rheological results...
2017: PloS One
https://www.readbyqxmd.com/read/28817708/timing-and-extent-of-finger-force-enslaving-during-a-dynamic-force-task-cannot-be-explained-by-emg-activity-patterns
#5
Mojtaba Mirakhorlo, Huub Maas, DirkJan H E J Veeger
Finger enslaving is defined as the inability of the fingers to move or to produce force independently. Such finger enslaving has predominantly been investigated for isometric force tasks. The aim of this study was to assess whether the extent of force enslaving is dependent on relative finger movements. Ten right-handed subjects (22-30 years) flexed the index finger while counteracting constant resistance forces (4, 6 and 8 N) orthogonal to the fingertip. The other, non-instructed fingers were held in extension...
2017: PloS One
https://www.readbyqxmd.com/read/28817611/the-directed-migration-of-gonadal-distal-tip-cells-in-caenorhabditis-elegans-requires-ngat-1-a-%C3%A3-1-4-n-acetylgalactosaminyltransferase-enzyme
#6
Joseph Veyhl, Robert J Dunn, Wendy L Johnston, Alexa Bennett, Lijia W Zhang, James W Dennis, Harry Schachter, Joseph G Culotti
Glycoproteins such as growth factor receptors and extracellular matrix have well-known functions in development and cancer progression, however, the glycans at sites of modification are often heterogeneous molecular populations which makes their functional characterization challenging. Here we provide evidence for a specific, discrete, well-defined glycan modification and regulation of a stage-specific cell migration in Caenorhabditis elegans. We show that a chain-terminating, putative null mutation in the gene encoding a predicted β1,4-N-acetylgalactosaminyltransferase, named ngat-1, causes a maternally rescued temperature sensitive (ts) defect in the second phase of the three phase migration pattern of the posterior, but not the anterior, hermaphrodite Distal Tip Cell (DTC)...
2017: PloS One
https://www.readbyqxmd.com/read/28817580/criticality-predicts-maximum-irregularity-in-recurrent-networks-of-excitatory-nodes
#7
Yahya Karimipanah, Zhengyu Ma, Ralf Wessel
A rigorous understanding of brain dynamics and function requires a conceptual bridge between multiple levels of organization, including neural spiking and network-level population activity. Mounting evidence suggests that neural networks of cerebral cortex operate at a critical regime, which is defined as a transition point between two phases of short lasting and chaotic activity. However, despite the fact that criticality brings about certain functional advantages for information processing, its supporting evidence is still far from conclusive, as it has been mostly based on power law scaling of size and durations of cascades of activity...
2017: PloS One
https://www.readbyqxmd.com/read/28817439/faculty-development-for-the-operating-room-an-examination-of-the-effectiveness-of-an-intraoperative-teaching-course-for-surgeons
#8
Aimee K Gardner, Matthew D Timberlake, Brian J Dunkin
OBJECTIVE: We describe a half-day faculty development course designed to equip surgical educators with evidence-based teaching frameworks shown to promote learning in the operating room (OR). We hypothesize that participating faculty will deliver improved instruction as perceived by residents. METHODS: Residents anonymously rated faculty teaching behaviors among whom they had recently worked in the OR (minimum 3 cases in preceding 6 months) using the Briefing - Intraoperative teaching - Debriefing Assessment Tool (BIDAT; 1 = never, 5 = always)...
August 16, 2017: Annals of Surgery
https://www.readbyqxmd.com/read/28817373/cabozantinib-as-salvage-therapy-for-patients-with-tyrosine-kinase-inhibitor-refractory-differentiated-thyroid-cancer-results-of-a-multicenter-phase-ii-international-thyroid-oncology-group-trial
#9
Maria E Cabanillas, Jonas A de Souza, Susan Geyer, Lori J Wirth, Michael E Menefee, Stephen V Liu, Komal Shah, John Wright, Manisha H Shah
Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib...
August 17, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28817371/phase-i-ii-trial-of-labetuzumab-govitecan-anti-ceacam5-sn-38-antibody-drug-conjugate-in-patients-with-refractory-or-relapsing-metastatic-colorectal-cancer
#10
Efrat Dotan, Steven J Cohen, Alexander N Starodub, Christopher H Lieu, Wells A Messersmith, Pamela S Simpson, Michael J Guarino, John L Marshall, Richard M Goldberg, J Randolph Hecht, William A Wegener, Robert M Sharkey, Serengulam V Govindan, David M Goldenberg, Jordan D Berlin
Purpose The objectives were to evaluate dosing schedules of labetuzumab govitecan, an antibody-drug conjugate targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for tumor delivery of 7-ethyl-10-hydroxycamptothecin (SN-38), in an expanded phase II trial of patients with relapsed or refractory metastatic colorectal cancer. Patients and Methods Eligible patients with at least one prior irinotecan-containing therapy received labetuzumab govitecan once weekly at 8 and 10 mg/kg, or two times per week at 4 and 6 mg/km on weeks 1 and 2 of 3-week repeated cycles...
August 17, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28817370/conko-005-adjuvant-chemotherapy-with-gemcitabine-plus-erlotinib-versus-gemcitabine-alone-in-patients-after-r0-resection-of-pancreatic-cancer-a-multicenter-randomized-phase-iii-trial
#11
Marianne Sinn, Marcus Bahra, Torsten Liersch, Klaus Gellert, Helmut Messmann, Wolf Bechstein, Dirk Waldschmidt, Lutz Jacobasch, Martin Wilhelm, Bettina M Rau, Robert Grützmann, Arndt Weinmann, Georg Maschmeyer, Uwe Pelzer, Jens M Stieler, Jana K Striefler, Michael Ghadimi, Sven Bischoff, Bernd Dörken, Helmut Oettle, Hanno Riess
Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m(2) days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles...
August 17, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28817311/beta-secretase-inhibitors-in-phase-i-and-phase-ii-clinical-trials-for-alzheimer-s-disease
#12
Charbel E-H Moussa
BACE 1 is a protease that cleaves the transmembrane amyloid precursor protein and generates amyloid-β peptides that accumulate in AD brains. No known mutations are identified in the gene encoding BACE1 in AD. However, enzyme levels are elevated in AD and a single residue mutation in amyloid precursor protein protects against protein cleavage by BACE1, suggesting BACE involvement in disease pathogenesis. Drugs that can inhibit BACE1 would theoretically prevent Aβ accumulation and halt AD onset and progression...
August 17, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28817287/visible-light-induced-oxidative-chlorination-of-alkyl-sp-3-c-h-bonds-with-nacl-oxone-at-room-temperature
#13
Mengdi Zhao, Wenjun Lu
A visible light-induced monochlorination of cyclohexane with sodium chloride (5:1) has been successfully accomplished to afford chlorocyclohexane in excellent yield by using Oxone as the oxidant in H2O/CF3CH2OH at room temperature. Other secondary and primary alkyl sp(3) C-H bonds of cycloalkanes and functional branch/linear alkanes can also be chlorinated, respectively, under similar conditions. The selection of a suitable organic solvent is crucial in these efficient radical chlorinations of alkanes in two-phase solutions...
August 17, 2017: Organic Letters
https://www.readbyqxmd.com/read/28817282/tnf-induced-switching-of-columnar-rectangular-to-hexagonal-assemblies-in-a-new-class-of-triphenylene-based-room-temperature-discotic-liquid-crystals
#14
Monika Gupta, Santosh Prasad Gupta, Santanu Kumar Pal
A straightforward synthesis of triphenylene-based oligomeric systems that self-organize into room temperature columnar structures is presented. The compounds with longer spacer length (m = 10 and 12) exhibit columnar rectangular (Colr) mesophase whereas the compound with m = 8 exists in glassy Colr state. Interestingly, the Colr self-assembly of these compounds switches to columnar hexagonal (Colh) on doping the compounds with 2, 4, 7-trinitrofluorenone (TNF). For the dopant concentration of 1:1 with respect to native compound, an intermediate transition state between Colr and Colh phase was observed which completely transformed into the hexagonal phase on increasing the concentration to 1:2 (compound: TNF) and afterwards...
August 17, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28817260/current-use-flame-retardants-in-the-water-of-lake-michigan-tributaries
#15
Jiehong Guo, Kevin Romanak, Stephen Westenbroek, Ronald A Hites, Marta Venier
In this study, we measured the concentrations of 65 flame retardants in water samples from five Lake Michigan tributaries. These flame retardants included organophosphate esters (OPEs), brominated flame retardants (BFRs), and Dechlorane-related compounds. A total of 59 samples, including both the particulate and the dissolved phases, were collected from the Grand, Kalamazoo, Saint Joseph, and Lower Fox rivers and from the Indiana Harbor and Ship Canal (IHSC) in 2015. OPEs were the most abundant among the targeted compounds with geometric mean concentrations ranging from 20 to 54 ng/L; OPE concentrations were comparable among the five tributaries...
August 17, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28817199/exposure-response-modeling-and-power-analysis-of-components-of-acr-response-criteria-in-rheumatoid-arthritis-part-1-binary-model
#16
Liang Li, Yi Zhang, Lian Ma, Ping Ji, Sarah Yim, Badrul Chowdhury, Suresh Doddapaneni, Jiang Liu, Yaning Wang, Chandrahas Sahajwalla
American College of Rheumatology (ACR) response criteria is used to assess improvement in tender and swollen joint counts and in 3 of the 5 core measures (acute-phase reactant, physician global assessment, patient global assessment, pain, and physical function). From the clinical trial data on 5 approved biological products for the treatment of rheumatoid arthritis, population pharmacokinetic/pharmacodynamic models were developed to quantitatively describe the relationship between exposure and response rates of 3 individual components of ACR response criteria...
September 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28817190/a-phase-1-and-2-study-of-filanesib-alone-and-in-combination-with-low-dose-dexamethasone-in-relapsed-refractory-multiple-myeloma
#17
Jatin J Shah, Jonathan L Kaufman, Jeffrey A Zonder, Adam D Cohen, William I Bensinger, Brandi W Hilder, Selena A Rush, Duncan H Walker, Brian J Tunquist, Kevin S Litwiler, Mieke Ptaszynski, Robert Z Orlowski, Sagar Lonial
BACKGROUND: Filanesib (ARRY-520) is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity. METHODS: This open-label Phase 1/2 study determined the maximum tolerated dose of Filanesib administered on Days 1 and 2 of 14-Day Cycles in patients with multiple myeloma (MM) and included expansion cohorts with and without dexamethasone (40 mg/week). Patients in the dose-escalation (N = 31) and Phase 2 single-agent (N = 32) cohorts had received prior bortezomib as well as prior thalidomide and/or lenalidomide...
August 17, 2017: Cancer
https://www.readbyqxmd.com/read/28817150/beryllium-based-fluorenes-as-efficient-anion-sponges
#18
M Merced Montero-Campillo, Inés Corral, Otilia Mó, Manuel Yáñez, Ibon Alkorta, José Elguero
The F(-), Cl(-), CN(-), NO2(-), NO3(-), and SO4(2-) anion affinities of 4,5-bis(BeX)-fluorene (X = H, F, Cl, CN, NC, and OCH3) derivatives have been calculated at the B3LYP/6-311+G(3df,2p)//B3LYP/6-31+G(d,p) level of theory. The reliability of this approach was assessed using, for some suitable cases, the accurate G4MP2 ab initio composite method as a reference. The values obtained indicate that these derivatives exhibit anion affinities which are among the largest ones reported for single neutral molecules, and therefore these compounds behave as anion sponges, very much as their 1,8-diBeX-naphthalene analogues...
August 17, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28817121/meganuclease-assisted-generation-of-stable-transgenics-in-the-sea-anemone-nematostella-vectensis
#19
Eduard Renfer, Ulrich Technau
The sea anemone Nematostella vectensis is a model system used by a rapidly growing research community for comparative genomics, developmental biology and ecology. Here, we describe a microinjection procedure for creating stable transgenic lines in Nematostella based on meganuclease (I-SceI)-assisted integration of a transgenic cassette into the genome. The procedure describes the preparation of the reagents, microinjection of the transgenesis vector and the husbandry of transgenic animals. The microinjection setup differs from those of previously published protocols by the use of a holding capillary mounted on an inverted fluorescence microscope...
September 2017: Nature Protocols
https://www.readbyqxmd.com/read/28817102/anticancer-activity-of-ramalin-a-secondary-metabolite-from-the-antarctic-lichen-ramalina-terebrata-against-colorectal-cancer-cells
#20
Sung-Suk Suh, Tai Kyoung Kim, Jung Eun Kim, Ju-Mi Hong, Trang Thu Thi Nguyen, Se Jong Han, Ui Joung Youn, Joung Han Yim, Il-Chan Kim
Colorectal cancer is a leading cause of death worldwide and occurs through the highly complex coordination of multiple cellular pathways, resulting in carcinogenesis. Recent studies have increasingly revealed that constituents of lichen extracts exhibit potent pharmaceutical activities, including anticancer activity against various cancer cells, making them promising candidates for new anticancer therapeutic drugs. The main objective of this study was to evaluate the anticancer capacities of ramalin, a secondary metabolite from the Antarctic lichen Ramalina terebrata, in the human colorectal cancer cell line HCT116...
August 17, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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